ToxSci Advance Access published online on February 14, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj131
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1 Department of Biomedical and Pharmaceutical Sciences and Center for Molecular Toxicology, University of Rhode Island, Kingston, RI 02881
* To whom correspondence should be addressed. Renal epithelial cells undergo apoptosis upon exposure to cadmium (Cd). Transcription factors, such as NF-
Received November 9, 2005
Accepted January 30, 2006
Systems Toxicology
Cadmium-Induced Apoptosis in Rat Kidney Epithelial Cells Involves Modulation of NF-
Jianxun Xie 1
and
Zahir A Shaikh 1 *
B Activity
Zahir A Shaikh, E-mail: zshaikh{at}uri.edu
Abstract 
B, mediate the expression of a number genes involved in apoptosis. The present study was designed to examine the involvement of this transcription factor in Cd-induced apoptosis. Rat kidney proximal tubular epithelial cells, NRK-52E, were incubated with up to 20 µM CdCl2 in serum-free medium for 5 h followed by incubation in serum-containing medium (without Cd) for an additional 12 h. The cells accumulated 582±19 ng Cd/mg protein after 5 h exposure to 20 µM Cd. As a result of Cd exposure, the DNA binding activity of p65 subunit of NF-B was decreased in a concentration- and time-dependent manner. The activity of TNF-
-induced IB kinase was also inhibited by Cd. In addition, the phosphorylation of IB and NF-B p65, as well as the levels of NF-B target gene products, cIAP-1 and cIAP-2, were reduced. Pretreatment of the cells with antioxidants, U8386E or BHT, preserved the DNA binding activity and blocked the Cd-induced decease in IB phosphorylation. Cd exposure casued the activation of caspase -3, -7 and -9 and DNA fragmentation. By flowcytometry, 14.6 and 30.5% apoptosis was detected at 6 and 12 h after stopping the Cd exposure. Overexpression of NF-B p65 by transient transfection protected the cells from the Cd-induced apoptosis. Conversely, attenuation of NF-B activity by pretreatment with SN50, an NF-B nuclear translocation inhibitor, potentiated apoptosis. These results suggest that Cd-induced apoptosis involves suppression of NF-B activity which may be mediated by oxidative stress.B); IKK; IB; IAPs; Apoptosis; Kidney; Epithelial cells; Oxidative stress.
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